SOCOM: U.S. Navy SEALs Tactical Strike is the third handheld game in the SOCOM series. In Tactical Strike, the player is in command of four combatants. Tactical Strike, SOCOM: U.S. Navy SEALs Confrontation and SOCOM: U.S. Navy SEALs Fireteam Bravo 3 are developed by Slant Six Games instead of original and now defunct developer, Zipper Interactive.

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SOCOM: U.S. Navy Seals Tactical Strike focuses on the player being able to maintain tight control of a four-man special operations squad. The game represents a major departure from the "run and gun" gameplay of the previous SOCOM games. In Tactical Strike, the player himself is never able to physically shoot, run, etc. Instead, he or she must tell the squad to do such actions. The player often has to evaluate a situation and then plan accordingly, usually having to incorporate some stealth into his or her movements. The squad is moved around using a "skimmer" (the analog stick of the PSP); the player can preview where the individual members of the squad will move to before they opt to actually move the team. The squad can be controlled from the points of view of different soldiers; additionally, the four man-team can be split up into two teams of two. The player can even choose to select an individual member of the squad. At the start of the campaign, the player chooses from one of nine special forces teams to command: the Australian SASR, the German KSK, the British SAS, the French GIGN, the U.S. Navy SEALs, the Spanish UOE, the South Korean 707th Special Missions Battalion, the Italian Col Moschin, or the Dutch KCT. Although the storyline of the campaign is the same for every team, the voice track is voiced by native speakers of the different languages (with English subtitles). Before each mission, the player can choose the loadout and accessories for each individual, upgrade each soldier's attributes with skill points obtained from previous missions (skill points are awarded for killing enemies and completing objectives), and choose one of two places to insert into the mission (if applicable).

An emergency occurs when a meeting between an ambassador from the player's country and Panama's Interior Minister is interrupted by insurgents, known as La Mano los Gente (The Hand of the People), who take the two men as hostages. When the ambassador's country becomes aware of the situation, a special forces team is inserted into Panama to resolve the hostage crisis. Initially, the special forces team's efforts are frustrated by the insurgents' frequent relocation of their hostages. However, they get a solid lead after tracking the movements of men under the command of La Mano leader and drug trafficker Cesar Rojas. Infiltrating a La Mano compound, the special forces team manages to eliminate the guards and rescue the Panamanian Interior Minister. He informs the team that the ambassador was also being held in the compound, but was moved when the team began their assault. After an infiltrating Cesar Rojas's home, analysis of his satellite phone shows that he has been in contact with ex-GRU Dimitry Lutchenko, who arrived in Panama a few weeks ago. During a mission to capture La Mano second-in-command Hector Ortiz, the insurgents are seen in a fierce firefight against black clad mercenaries. While being interrogated, Ortiz reveals he has ordered his troops to plant explosives at a pumping station along the Trans-Isthmus Oil pipeline, the destruction of which would cause severe economic and environmental damage to Panama. Fortunately, the special forces Team is able to intervene and, with the help of a pair of engineers, disable the explosive charges while fighting off La Mano forces. It is later learned that the mercenaries who attacked Ortiz's men, known as the “Wolf Brigade,” are under the command of Lutchenko, who is in turn in the employ of Alexander Volchkov, a known arms dealer and CEO of Petroskya Oil and Gas. After being tipped off by an informant, the special forces team faces off against more armed insurgents, and is finally able to capture Cesar Rojas. Rojas reveals that he made a deal with Volchkov: in return for money and weapons, he agreed to have La Mano sabotage key pieces of Panamanian oil infrastructure. This would interrupt the supply and delivery of oil, allowing Voltchkov to profit off of the situation. Rojas also reveals that Lutchenko, who still has the ambassador in his possession, has taken over a hotel with his Wolf Brigade. Taking out a large number of Wolf Brigade forces, the special forces team successfully infiltrates the hotel and secures the ambassador. Lutchenko manages to slip away and leaves behind Wolf Brigade reinforcements to tie up the ambassador's rescue. This proves futile, as the ambassador is successfully extracted. Satellite tracking follows Lutchenko to the Panama Canal, where he plans to use explosives on a ship currently in the canal. This would shut down the canal indefinitely, resulting in incalculable damage to the world economy. Despite being heavily outnumbered, the special forces team disables bombs on both the ship itself and a nearby dam, fights off Wolf Brigade mercenaries, and subdues Dimitry Lutchenko. As an epilogue, a newscast reveals that Cesar Rojas and Hector Ortiz have been charged for their crimes, and that Panama has entered talks with NATO regarding regional security, both encouraging a drop in oil prices on the world markets. Alexander Volchkov, surprisingly evading punishment for his role in the Panamanian incident, appears at a shareholders' meeting for Petroskya Oil and Gas, promising a bright future for the company.